- Email: [email protected]
Circadian rhythm disorder in a rare disease: Smith–Magenis syndrome
Molecular and Cellular Endocrinology 252 (2006) 88–91
Circadian rhythm disorder in a rare disease: Smith–Magenis syndrome H´el`ene De Leersnyder a,∗ , Bruno Claustrat b , Arnold Munnich c , Alain Verloes a a
Department of Genetics, Hospital Robert Debr´e, 75019 Paris, France b Nuclear Medicine Center, Neurologic Hospital, Lyon, France c Department of Genetics, Hospital Necker Enfants-Malades, Paris, France
Abstract Smith–Magenis syndrome (SMS) is a clinically recognizable contiguous gene syndrome, caused by interstitial deletion of chromosome 17p11.2. The SMS phenotype include distinctive facial features, developmental delay and neurobehavioral abnormalities. The patients present major sleep disturbances ascribed to a phase shift of their circadian rhythm of melatonin with a paradoxical diurnal secretion of the hormone. Treatment with morning beta-blockers and evening melatonin reinstated a normally timed melatonin circadian rhythm, improved daytime behavior and restored normal sleep habits, resulting in a greatly improved quality of life for both SMS patients and their family. SMS is the demonstration of biological basis for sleep disorder in a genetic disease. Considering that clock genes mediate generation of circadian rhythms, we suggest that haploinsufficiency for a circadian system gene mapping to chromosome 17p11.2 may cause the inversion of circadian rhythm in SMS. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Smith–Magenis syndrome; Melatonin; Circadian rhythm; Beta-blockers
1. Introduction Smith–Magenis syndrome (SMS) is a rare genetic disease emblematic of neurodevelopmental disorder. The SMS phenotype includes mild dysmorphism, developmental delay and abnormal behavior. Severe sleep disturbances and maladaptive daytime behavior were linked to abnormal circadian rhythm of melatonin. SMS is the demonstration of biological basis for sleep disorder in a genetic disease. First described by Ann Smith et al. in 1982 (Smith et al., 1986; Greenberg et al., 1991), SMS is a contiguous gene deletion syndrome ascribed to interstitial deletion of chromosome 17 (17p11.2) (Juyal et al., 1996). However, deletions have ranged from <2 to >9 megabases and mutations in RAI1 (Retinoic AcidInduced gene) were shown in individuals who have phenotypic features consistent with SMS (Slager et al., 2003). The birth incidence is reported at 1/25,000 live births. All cases occur de novo, there is no parental imprinting. 2. Clinical features and diagnosis criteria Several distinctive features characterize the phenotype of Smith–Magenis syndrome (Smith et al., 1998a), including ∗
Corresponding author. Tel.: +33 140 035 342; fax: +33 140 035 344. E-mail address: [email protected] (H. De Leersnyder).
0303-7207/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mce.2006.03.043
brachycephaly with midface hypoplasia, mouth characteristic with cupid’s bow, ocular abnormalities, speech delay with or without hearing loss, hoarse deep voice, short stature, brachydactyly. Other variable features include cardiac defects, renal abnormalities, seizures, peripheral neuropathy, scoliosis, cleft palate, low immunoglobulins and thyroxin defect. Decreased sensitivity to pain was ascribed to anatomical and functional brain anomalies (Boddaert et al., 2004) All patients have some degree of developmental delay and mental retardation. IQ scores range between 20 and 78. Behavioral problems include consistently hyperactivity with attention deficit, aggression, self injurious behaviors, temper tantrums. Severe sleep disturbances (Smith et al., 1998b) and unusual circadian rhythms are constant features of the syndrome. The diagnosis is based on clinical features and confirmed on high resolution karyotype with detectable deletion of 17p11.2 and by fluorescence in situ hybridization (FISH) probe specific for SMS (Lucas et al., 2001). 3. Night and day sleep disturbances in Smith–Magenis syndrome The behavioral phenotype includes significant sleep disturbance and have a major impact on the child and other family members, many of whom become sleep deprived themselves. Questionnaires, sleep consultations, sleep diaries and actimetric recordings revealed sleep disturbance in most SMS subjects. All
H. De Leersnyder et al. / Molecular and Cellular Endocrinology 252 (2006) 88–91
patients go to bed easily after a short bed-time ritual. Bedtime is similar at 8–9 p.m. regardless of age and sex. The duration of night sleep average 7.30 h. All SMS persons consistently wake up one to three times per night and fall back asleep within 30 min or more. Once awaken, they are hyperactive. This behavior force parents or care keeping to constantly look after them and to devise artifices to keep them in the bedroom by night (lock the door, switch light, remove furniture and objects). The mean wake-up time is 5.30 a.m. Behavioral problems correlate with night sleep insufficiency. Most patients exhibit morning tiredness when normally circadian vigilance is high. They have temper tantrums when tired and naps (more than 30 min) during the day, regardless of age. Most interestingly, they consistently have “sleep attacks” at the end of the day. The 24 h-polysomnography, correlated with actimetry and sleep diaries, reveal a reduced total sleep time in 57% of the patients. All sleep stages are present but stage 3–4 non-rapid eye movement (NREM) sleep is reduced. REM sleep is disrupted and arousals with increased tonic EMG activity are frequent. Prolonged awakenings occur in 75% of cases. Interestingly, all SMS patients display a phase shift in their circadian rhythm of melatonin (De Leersnyder et al., 2001a,b) (Fig. 1). Indeed, time at onset of melatonin secretion in SMS is 6 a.m. ± 2 (controls: 9 p.m. ± 2), peak time is at 12 p.m. ± 1 (controls: 3:30 a.m. ± 1.30) and melatonin offset is at 8 p.m. ± 1 (controls: 6 a.m. ± 1). Melatonin peak value rises 94 ± pg/ml (controls: 76 pg/ml). Irregular levels of melatonin are noted during the day with a second peak between 6 and 8 p.m. (45 pg/ml ± 32) and the total duration of melatonin secretion is protracted in SMS: 15.5 h ± 3.5 (controls: 8 h ± 1). Similarly urinary melatonin and 6-sulfatoxymelatonin revealed an inverted night/day ratio (Potocki et al., 2000). Cortisol, growth hormone (GH) and prolactin follow a usual circadian secretion and are in the normal range. This abnormal circadian rhythm of melatonin parallels sleep disturbances and abnormal day behavior in SMS (Fig. 2). During the night, early sleep onset, frequent awakenings and early sleep offset are consistent features of the disease and are highly specific diagnostic criteria in SMS. The sleep attacks occurring at the end of the day may represent in fact the endogenous sleep onset of the patient that could be regarded therefore as equivalent to a sleep phase advance. According to this hypothesis, the endogenous sleep onset time would be masked by the imposed social activities. During the day patients are tired in the morning and tantrums appears when melatonin rises. Naps and sleep attacks occur when melatonin peaks at midday and in the evening, respectively. Considering that behavioral problems correlate with the abnormal circadian rhythm of melatonin in SMS, it is tempting to hypothesize that at least part of hyperactivity and attention deficit occur because the patients struggled against sleep when melatonin rise during the day.
Fig. 1. Circadian variation of cortisol, growth hormone and melatonin in Smith–Magenis syndrome and controls. Aged-matched controls were healthy children or adolescents.
4. Hypothesis concerning melatonin dysfunction Melatonin, the main hormone of the pineal gland, is synthesized from serotonin. Its synthesis and release are stimulated
89
Fig. 2. Sleep–wake patterns correlated with melatonin secretion in SMS.
90
H. De Leersnyder et al. / Molecular and Cellular Endocrinology 252 (2006) 88–91
by darkness and inhibited by light. Light entrainment proceeds through the retino-hypothalamic tract (RHT) to reach the suprachiasmatic nuclei (SCN) of the anterior hypothalamus (Moore, 1997). SCN contain biological clocks, which are endogenous pacemakers generating circadian rhythms entrained by environmental stimuli. A number of clock genes controlling circadian rhythms have been recently identified in higher eukaryotes (Van Esseveldt et al., 2000). Their expression shares common features across species, it oscillates with a 24-h rhythm and persists in the absence of environmental cues. It is reset by changes in light/dark cycle and undergoes negative feedback that down-regulates their activity. Considering that clock genes are expressed in a circadian pattern in SCN, one can hypothesize that haploinsufficiency for a clock gene could account for sleep disturbance in SMS. The Per1 gene, which maps to chromosome 17p12 is not deleted in SMS. Interestingly, subunit 3 of the COP9 signal transduction complex (COPS3) maps within the SMS critical region in 17p11.2 (Potocki et al., 1999). COP9 is essential for the light control of gene expression during plant development and is conserved across species. It has been shown that the gene for subunit 3 of the COP9 signal transduction complex, COPS3, is expressed in transformed lymphoblastoid cell lines of SMS patients. However, haploinsufficiency in one gene probably does not play a significant role with respect to melatonin phase shift in SMS, there may be an age dependent penetrance or variability of the expression of the phenotype (embryological changes). Circadian rhythmicity not only involves clock genes but also requires an input signaling pathway for detection of exogenous signals (zeitgeber) and their transmission to SCN via the RHT, and an output signaling pathway of postganglionic fibers ascending to the pineal gland is required to maintain melatonin secretion under the control of the SCN. Consequently, the inversion of the circadian rhythm of melatonin in SMS may also result from an alteration of the input/output-signaling pathway (e.g. photic entrainment in the retina/RHT or 1-adrenergic signaling transduction to the pineal gland). Actually, the mechanism of this quantitatively normal but rhythmically abnormal melatonin secretion in SMS is not known. 5. Treatment of the inverted rhythm of melatonin in Smith–Magenis syndrome We hypothesized that behavioral problems and night sleep insufficiency in SMS may correlate with the inverted circadian rhythm of melatonin. Sleep disturbances are extremely severe and difficult to manage. These observations are particularly relevant to therapeutic approaches in SMS. Indeed the circadian rhythm of melatonin is controlled by the sympathetic nervous system and it is known that 1 -adrenergic antagonists reduce the production of melatonin (Stoschitzky et al., 1999). An original therapeutic approach including blockade of endogenous melatonin signaling pathways combined with on-time exogenous melatonin administration was studied in patients aged 6–18 years (De Leersnyder et al., 2001a,b, 2003). A cardiac and pneumologic examination was performed before trial. After a morning 1 -adrenergic antagonists administration, plasma melatonin
Fig. 3. Circadian variation of plasma melatonin before (J1) and after morning beta adrenergic antagonist administration (J2–J3) and control release melatonin administration (J3).
levels rapidly decreased in all SMS patients. Mean melatonin levels fell from 68 to 8 pg/ml after drug administration. Individual melatonin levels decreased 3–20-fold, remained low from 8 a.m. to 6 a.m. the next day and rose again from 6 to 8 a.m. prior to drug administration (Fig. 3). With this treatment, day behavior markedly improved. While untreated patients had 1–3 naps/day and frequent sleep attacks at the end of the day, beta-blocker administration resulted in the disappearance of naps and sleep attacks. The explosive tantrums (1–2 each day) were less frequent (1 or 2 per week) and could be easily managed. Concentration increased during school time and children were reported to be quieter and less hyperactive. No significant increase of cognitive performance was observed. The combination of morning 1 -adrenergic antagonist and evening melatonin administration restored plasmatic circadian melatonin rhythmicity, improved behavioral disturbances and enhanced sleep in SMS. Studies were conducted with a control release (CR) melatonin (De Leersnyder et al., 2003). After a single dose of exogenous melatonin, plasmatic melatonin levels rapidly peaked and slowly decreased thus mimicking the effects of endogenous melatonin on circadian rhythm. Mean melatonin levels rose from 12.7 ± 10.6 to 2189 ± 1800 pg/ml 2 h after drug administration. Individual melatonin levels increased 170-fold compared to levels after 1 -adrenergic antagonists administration, remained high from 10 p.m. to 2 a.m., and slowly decreased till 6 a.m. (Fig. 3). Mean sleep onset was delayed by 30 min, sleep offset by 60 min and the mean gain of sleep was 30 min. Sleep awakenings disappeared in most cases and wake-up time was delayed. Patients no more woke up during the night and EEG recordings confirmed a more regular sleep stage organization and a rapid access to sleep stage 3–4. Sleep was deep and quiet and day/night life was dramatically improved. No desensitization was observed over a 3 years period of drug administration. As this treatment restored a biological rhythm when it was inverted, it is proposed for most SMS patients, in respect of contraindication. Finally, there were no adverse events related to the treatment, no side effects or habituation, and children, parents and care giving were convinced for continuation of the treatment.
H. De Leersnyder et al. / Molecular and Cellular Endocrinology 252 (2006) 88–91
6. Conclusion Smith–Magenis syndrome is a rare genetic disorder ascribed to interstitial deletion of chromosome 17 (17p11.2). SMS is also a circadian disorder with extreme phase shift of melatonin secretion. This is the first biological model of sleep and behavioral disorders in a genetic disease. Elucidating pathophysiological mechanisms of behavioral phenotypes is particularly relevant to therapeutic approach in genetic diseases. Indeed, in SMS where the circadian rhythm of melatonin is shifted, 1 -adrenergic antagonists combined with evening melatonin administration restore a circadian rhythm of melatonin, suppress inappropriate diurnal melatonin secretion and improve sleep and behavioral disorders. Acknowledgments We are grateful to the individuals, parents and the ASM 17 family support group of France for participating in the studies. We thank Marie Christine de Blois, Jean Louis Bresson, Daniel Sidi, Jean Claude Souberbielle for their assistance with the studies in the Necker-Enfants Malades Hospital, Paris, France; Ann Smith and Wallace Duncan in the NIH SMS Research Unit for helpfull cooperation. The studies were supported in part by Institut de Recherche Internationales Servier, Paris, France and Neurim, Pharmaceuticals, Tel Aviv, Isra¨el. References Boddaert, N., De Leersnyder, H., Bourgeaois, M., Munnich, A., Brunelle, F., Zilbovicius, M., 2004. Anatomical and functional brain imaging evidence of lenticulo-insular anomalies in Smith–Magenis syndrome. Neuroimage 21, 1021–1025. De Leersnyder, H., de Blois, M.-C., Claustrat, B., Romana, S., Albrecht, U., von Kleist-Retzow, J.-C., Delobel, B., Viot, G., Lyonnet, S., Vekemans, M., Munnich, A., 2001a. Inversion of the circadian rhythm of melatonin in the Smith–Magenis syndrome. J. Pediat. 139, 111–116. De Leersnyder, H., de Blois, M.-C., Vekemans, M., Sidi, D., Villain, E., Kindermans, C., Munnich, A., 2001b. Beta-1-adrenergic antagonists improve sleep and behavioural disturbances in a circadian disorder Smith–Magenis syndrome. J. Med. Genet. 38, 586–590.
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De Leersnyder, H., Bresson, J.L., de Blois, M.-C., Souberbielle, J.C., Mogenet, A., Delhotal-Landes, B., Salefranque, F., Munnich, A., 2003. Beta-1-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith–Magenis syndrome. J. Med. Genet. 40, 74–78. Greenberg, F., Guzzetta, V., de Oca-Luna, R.M., Magenis, R.E., Smith, A.C.M., Richter, S.F., Kondo, I., Dobyns, W.B., Patel, P.I., Lupski, J.R., 1991. Molecular analysis of the Smith–Magenis syndrome: a possible contiguous-gene syndrome associated with del(17)(p11.2). Am. J. Hum. Genet 49, 1207–1218. Juyal, R.C., Figuera, L.E., Hauge, X., Elsea, S.H., Lupski, J.R., Greenberg, F., Baldini, A., Patel, P.I., 1996. Molecular analysis of 17p11.2 deletion in 62 Smith–Magenin syndrome patients. Am. J. Hum.Genet. 58, 998– 1007. Lucas, R.E., Vlangos, C.N., Das, P., Patel, P.I., Elsea, S.H., 2001. Genomic organisation of the ∼1.5 Mb Smith–Magenis syndrome critical interval: transcription map, genomic contig, and candidate gene analysis. Eur. J. Hum. Genet. 9, 892–902. Moore, R.Y., 1997. Circadian rhythms: basic neurobiology and clinical applications. Annu. Rev. Med. 48, 253–266. Potocki, L., Chen, K.S., Lupski, J., 1999. Subunit 3 of the COP9 signal transduction complex is conserved from plants to humans and maps within the Smith–Magenis syndrome critical region in 17p11.2. Genomics 57, 180–182. Potocki, L., Glaze, D., Tan, D.-X., Park, S.-S., Kashork, C.D., Shaffer, L.G., Reiter, R.J., Lupski, J.R., 2000. Circadian rhythm abnormalities of melatonin in Smith–Magenis syndrome. J. Med. Genet. 37, 428– 433. Slager, R.E., Newton, T.L., Vlangos, C.N., Finucane, B., Elsea, S.H., 2003. Mutations in RAI1 associated with Smith–Magenis syndrome. Nat. Genet 33, 466–468. Smith, A.C.M., McGavran, L., Robinson, J., Waldstein, G., Macfarlane, J., Zonana, J., Reiss, J., Lahr, M., Allen, L., Magenis, E., 1986. Interstitial deletion of (17)(p11.2p11.2) in nine patients. Am. J. Med. Genet. 24, 393–414. Smith, A.C.M., Dykens, E., Greenberg, F., 1998a. Behavioral phenotype of Smith–Magenis syndrome (del 17p11.2). Am. J. Med. Genet. 81, 179–185. Smith, A.C.M., Dykens, E., Greenberg, F., 1998b. Sleep disturbance in Smith–Magenis syndrome (del 17p11.2). Am. J. Med. Genet. 81, 186–191. Stoschitzky, K., Sakotnik, A., Lercher, P., Sweiker, R., Maier, R., Liebmann, P., Lindner, W., 1999. Influence of beta blockers on melatonin release. Eur. J. Clin. Pharmacol. 55, 111–115. Van Esseveldt, L.E., Lehman, M.N., Boer, G.J., 2000. The suprachiasmatic nucleus and the circadian time-keeping system revisited. Brain Res. Rev. 33, 34–77.
Circadian rhythm disorder in a rare disease: Smith–Magenis syndrome H´el`ene De Leersnyder a,∗ , Bruno Claustrat b , Arnold Munnich c , Alain Verloes a a
Department of Genetics, Hospital Robert Debr´e, 75019 Paris, France b Nuclear Medicine Center, Neurologic Hospital, Lyon, France c Department of Genetics, Hospital Necker Enfants-Malades, Paris, France
Abstract Smith–Magenis syndrome (SMS) is a clinically recognizable contiguous gene syndrome, caused by interstitial deletion of chromosome 17p11.2. The SMS phenotype include distinctive facial features, developmental delay and neurobehavioral abnormalities. The patients present major sleep disturbances ascribed to a phase shift of their circadian rhythm of melatonin with a paradoxical diurnal secretion of the hormone. Treatment with morning beta-blockers and evening melatonin reinstated a normally timed melatonin circadian rhythm, improved daytime behavior and restored normal sleep habits, resulting in a greatly improved quality of life for both SMS patients and their family. SMS is the demonstration of biological basis for sleep disorder in a genetic disease. Considering that clock genes mediate generation of circadian rhythms, we suggest that haploinsufficiency for a circadian system gene mapping to chromosome 17p11.2 may cause the inversion of circadian rhythm in SMS. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Smith–Magenis syndrome; Melatonin; Circadian rhythm; Beta-blockers
1. Introduction Smith–Magenis syndrome (SMS) is a rare genetic disease emblematic of neurodevelopmental disorder. The SMS phenotype includes mild dysmorphism, developmental delay and abnormal behavior. Severe sleep disturbances and maladaptive daytime behavior were linked to abnormal circadian rhythm of melatonin. SMS is the demonstration of biological basis for sleep disorder in a genetic disease. First described by Ann Smith et al. in 1982 (Smith et al., 1986; Greenberg et al., 1991), SMS is a contiguous gene deletion syndrome ascribed to interstitial deletion of chromosome 17 (17p11.2) (Juyal et al., 1996). However, deletions have ranged from <2 to >9 megabases and mutations in RAI1 (Retinoic AcidInduced gene) were shown in individuals who have phenotypic features consistent with SMS (Slager et al., 2003). The birth incidence is reported at 1/25,000 live births. All cases occur de novo, there is no parental imprinting. 2. Clinical features and diagnosis criteria Several distinctive features characterize the phenotype of Smith–Magenis syndrome (Smith et al., 1998a), including ∗
Corresponding author. Tel.: +33 140 035 342; fax: +33 140 035 344. E-mail address: [email protected] (H. De Leersnyder).
0303-7207/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mce.2006.03.043
brachycephaly with midface hypoplasia, mouth characteristic with cupid’s bow, ocular abnormalities, speech delay with or without hearing loss, hoarse deep voice, short stature, brachydactyly. Other variable features include cardiac defects, renal abnormalities, seizures, peripheral neuropathy, scoliosis, cleft palate, low immunoglobulins and thyroxin defect. Decreased sensitivity to pain was ascribed to anatomical and functional brain anomalies (Boddaert et al., 2004) All patients have some degree of developmental delay and mental retardation. IQ scores range between 20 and 78. Behavioral problems include consistently hyperactivity with attention deficit, aggression, self injurious behaviors, temper tantrums. Severe sleep disturbances (Smith et al., 1998b) and unusual circadian rhythms are constant features of the syndrome. The diagnosis is based on clinical features and confirmed on high resolution karyotype with detectable deletion of 17p11.2 and by fluorescence in situ hybridization (FISH) probe specific for SMS (Lucas et al., 2001). 3. Night and day sleep disturbances in Smith–Magenis syndrome The behavioral phenotype includes significant sleep disturbance and have a major impact on the child and other family members, many of whom become sleep deprived themselves. Questionnaires, sleep consultations, sleep diaries and actimetric recordings revealed sleep disturbance in most SMS subjects. All
H. De Leersnyder et al. / Molecular and Cellular Endocrinology 252 (2006) 88–91
patients go to bed easily after a short bed-time ritual. Bedtime is similar at 8–9 p.m. regardless of age and sex. The duration of night sleep average 7.30 h. All SMS persons consistently wake up one to three times per night and fall back asleep within 30 min or more. Once awaken, they are hyperactive. This behavior force parents or care keeping to constantly look after them and to devise artifices to keep them in the bedroom by night (lock the door, switch light, remove furniture and objects). The mean wake-up time is 5.30 a.m. Behavioral problems correlate with night sleep insufficiency. Most patients exhibit morning tiredness when normally circadian vigilance is high. They have temper tantrums when tired and naps (more than 30 min) during the day, regardless of age. Most interestingly, they consistently have “sleep attacks” at the end of the day. The 24 h-polysomnography, correlated with actimetry and sleep diaries, reveal a reduced total sleep time in 57% of the patients. All sleep stages are present but stage 3–4 non-rapid eye movement (NREM) sleep is reduced. REM sleep is disrupted and arousals with increased tonic EMG activity are frequent. Prolonged awakenings occur in 75% of cases. Interestingly, all SMS patients display a phase shift in their circadian rhythm of melatonin (De Leersnyder et al., 2001a,b) (Fig. 1). Indeed, time at onset of melatonin secretion in SMS is 6 a.m. ± 2 (controls: 9 p.m. ± 2), peak time is at 12 p.m. ± 1 (controls: 3:30 a.m. ± 1.30) and melatonin offset is at 8 p.m. ± 1 (controls: 6 a.m. ± 1). Melatonin peak value rises 94 ± pg/ml (controls: 76 pg/ml). Irregular levels of melatonin are noted during the day with a second peak between 6 and 8 p.m. (45 pg/ml ± 32) and the total duration of melatonin secretion is protracted in SMS: 15.5 h ± 3.5 (controls: 8 h ± 1). Similarly urinary melatonin and 6-sulfatoxymelatonin revealed an inverted night/day ratio (Potocki et al., 2000). Cortisol, growth hormone (GH) and prolactin follow a usual circadian secretion and are in the normal range. This abnormal circadian rhythm of melatonin parallels sleep disturbances and abnormal day behavior in SMS (Fig. 2). During the night, early sleep onset, frequent awakenings and early sleep offset are consistent features of the disease and are highly specific diagnostic criteria in SMS. The sleep attacks occurring at the end of the day may represent in fact the endogenous sleep onset of the patient that could be regarded therefore as equivalent to a sleep phase advance. According to this hypothesis, the endogenous sleep onset time would be masked by the imposed social activities. During the day patients are tired in the morning and tantrums appears when melatonin rises. Naps and sleep attacks occur when melatonin peaks at midday and in the evening, respectively. Considering that behavioral problems correlate with the abnormal circadian rhythm of melatonin in SMS, it is tempting to hypothesize that at least part of hyperactivity and attention deficit occur because the patients struggled against sleep when melatonin rise during the day.
Fig. 1. Circadian variation of cortisol, growth hormone and melatonin in Smith–Magenis syndrome and controls. Aged-matched controls were healthy children or adolescents.
4. Hypothesis concerning melatonin dysfunction Melatonin, the main hormone of the pineal gland, is synthesized from serotonin. Its synthesis and release are stimulated
89
Fig. 2. Sleep–wake patterns correlated with melatonin secretion in SMS.
90
H. De Leersnyder et al. / Molecular and Cellular Endocrinology 252 (2006) 88–91
by darkness and inhibited by light. Light entrainment proceeds through the retino-hypothalamic tract (RHT) to reach the suprachiasmatic nuclei (SCN) of the anterior hypothalamus (Moore, 1997). SCN contain biological clocks, which are endogenous pacemakers generating circadian rhythms entrained by environmental stimuli. A number of clock genes controlling circadian rhythms have been recently identified in higher eukaryotes (Van Esseveldt et al., 2000). Their expression shares common features across species, it oscillates with a 24-h rhythm and persists in the absence of environmental cues. It is reset by changes in light/dark cycle and undergoes negative feedback that down-regulates their activity. Considering that clock genes are expressed in a circadian pattern in SCN, one can hypothesize that haploinsufficiency for a clock gene could account for sleep disturbance in SMS. The Per1 gene, which maps to chromosome 17p12 is not deleted in SMS. Interestingly, subunit 3 of the COP9 signal transduction complex (COPS3) maps within the SMS critical region in 17p11.2 (Potocki et al., 1999). COP9 is essential for the light control of gene expression during plant development and is conserved across species. It has been shown that the gene for subunit 3 of the COP9 signal transduction complex, COPS3, is expressed in transformed lymphoblastoid cell lines of SMS patients. However, haploinsufficiency in one gene probably does not play a significant role with respect to melatonin phase shift in SMS, there may be an age dependent penetrance or variability of the expression of the phenotype (embryological changes). Circadian rhythmicity not only involves clock genes but also requires an input signaling pathway for detection of exogenous signals (zeitgeber) and their transmission to SCN via the RHT, and an output signaling pathway of postganglionic fibers ascending to the pineal gland is required to maintain melatonin secretion under the control of the SCN. Consequently, the inversion of the circadian rhythm of melatonin in SMS may also result from an alteration of the input/output-signaling pathway (e.g. photic entrainment in the retina/RHT or 1-adrenergic signaling transduction to the pineal gland). Actually, the mechanism of this quantitatively normal but rhythmically abnormal melatonin secretion in SMS is not known. 5. Treatment of the inverted rhythm of melatonin in Smith–Magenis syndrome We hypothesized that behavioral problems and night sleep insufficiency in SMS may correlate with the inverted circadian rhythm of melatonin. Sleep disturbances are extremely severe and difficult to manage. These observations are particularly relevant to therapeutic approaches in SMS. Indeed the circadian rhythm of melatonin is controlled by the sympathetic nervous system and it is known that 1 -adrenergic antagonists reduce the production of melatonin (Stoschitzky et al., 1999). An original therapeutic approach including blockade of endogenous melatonin signaling pathways combined with on-time exogenous melatonin administration was studied in patients aged 6–18 years (De Leersnyder et al., 2001a,b, 2003). A cardiac and pneumologic examination was performed before trial. After a morning 1 -adrenergic antagonists administration, plasma melatonin
Fig. 3. Circadian variation of plasma melatonin before (J1) and after morning beta adrenergic antagonist administration (J2–J3) and control release melatonin administration (J3).
levels rapidly decreased in all SMS patients. Mean melatonin levels fell from 68 to 8 pg/ml after drug administration. Individual melatonin levels decreased 3–20-fold, remained low from 8 a.m. to 6 a.m. the next day and rose again from 6 to 8 a.m. prior to drug administration (Fig. 3). With this treatment, day behavior markedly improved. While untreated patients had 1–3 naps/day and frequent sleep attacks at the end of the day, beta-blocker administration resulted in the disappearance of naps and sleep attacks. The explosive tantrums (1–2 each day) were less frequent (1 or 2 per week) and could be easily managed. Concentration increased during school time and children were reported to be quieter and less hyperactive. No significant increase of cognitive performance was observed. The combination of morning 1 -adrenergic antagonist and evening melatonin administration restored plasmatic circadian melatonin rhythmicity, improved behavioral disturbances and enhanced sleep in SMS. Studies were conducted with a control release (CR) melatonin (De Leersnyder et al., 2003). After a single dose of exogenous melatonin, plasmatic melatonin levels rapidly peaked and slowly decreased thus mimicking the effects of endogenous melatonin on circadian rhythm. Mean melatonin levels rose from 12.7 ± 10.6 to 2189 ± 1800 pg/ml 2 h after drug administration. Individual melatonin levels increased 170-fold compared to levels after 1 -adrenergic antagonists administration, remained high from 10 p.m. to 2 a.m., and slowly decreased till 6 a.m. (Fig. 3). Mean sleep onset was delayed by 30 min, sleep offset by 60 min and the mean gain of sleep was 30 min. Sleep awakenings disappeared in most cases and wake-up time was delayed. Patients no more woke up during the night and EEG recordings confirmed a more regular sleep stage organization and a rapid access to sleep stage 3–4. Sleep was deep and quiet and day/night life was dramatically improved. No desensitization was observed over a 3 years period of drug administration. As this treatment restored a biological rhythm when it was inverted, it is proposed for most SMS patients, in respect of contraindication. Finally, there were no adverse events related to the treatment, no side effects or habituation, and children, parents and care giving were convinced for continuation of the treatment.
H. De Leersnyder et al. / Molecular and Cellular Endocrinology 252 (2006) 88–91
6. Conclusion Smith–Magenis syndrome is a rare genetic disorder ascribed to interstitial deletion of chromosome 17 (17p11.2). SMS is also a circadian disorder with extreme phase shift of melatonin secretion. This is the first biological model of sleep and behavioral disorders in a genetic disease. Elucidating pathophysiological mechanisms of behavioral phenotypes is particularly relevant to therapeutic approach in genetic diseases. Indeed, in SMS where the circadian rhythm of melatonin is shifted, 1 -adrenergic antagonists combined with evening melatonin administration restore a circadian rhythm of melatonin, suppress inappropriate diurnal melatonin secretion and improve sleep and behavioral disorders. Acknowledgments We are grateful to the individuals, parents and the ASM 17 family support group of France for participating in the studies. We thank Marie Christine de Blois, Jean Louis Bresson, Daniel Sidi, Jean Claude Souberbielle for their assistance with the studies in the Necker-Enfants Malades Hospital, Paris, France; Ann Smith and Wallace Duncan in the NIH SMS Research Unit for helpfull cooperation. The studies were supported in part by Institut de Recherche Internationales Servier, Paris, France and Neurim, Pharmaceuticals, Tel Aviv, Isra¨el. References Boddaert, N., De Leersnyder, H., Bourgeaois, M., Munnich, A., Brunelle, F., Zilbovicius, M., 2004. Anatomical and functional brain imaging evidence of lenticulo-insular anomalies in Smith–Magenis syndrome. Neuroimage 21, 1021–1025. De Leersnyder, H., de Blois, M.-C., Claustrat, B., Romana, S., Albrecht, U., von Kleist-Retzow, J.-C., Delobel, B., Viot, G., Lyonnet, S., Vekemans, M., Munnich, A., 2001a. Inversion of the circadian rhythm of melatonin in the Smith–Magenis syndrome. J. Pediat. 139, 111–116. De Leersnyder, H., de Blois, M.-C., Vekemans, M., Sidi, D., Villain, E., Kindermans, C., Munnich, A., 2001b. Beta-1-adrenergic antagonists improve sleep and behavioural disturbances in a circadian disorder Smith–Magenis syndrome. J. Med. Genet. 38, 586–590.
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